兰州大学机构库 >学院待认领
高胰岛素抑制肾脏尿酸排泄的基础与临床研究以及氯沙坦的干预机制
Alternative TitleBasic and Clinical Study about the High Insulin Suppressed Renal Excretion of Uric Acid and the Intervention Mechanics of Losartan
黄文辉
Thesis Advisor刘静
2015-11-24
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name博士
Keyword氯沙坦 代谢综合征 胰岛素 高胰岛素血症 高尿酸血症 肾脏尿酸排泄 HK-2细胞 URAT1 PI3K/Akt1信号通路
Abstract目的:临床横断面分析来观察MetS患者血胰岛素与肾脏尿酸排泄之间的关系,体外实验证实高胰岛素对HK-2细胞URAT1表达及PI3K/Akt1信号通路的影响,探讨氯沙坦的干预作用。 结果:1.随着空腹血胰岛素水平的升高,FEUA明显呈下降趋势;随着餐后血胰岛素水平的升高,24hUUA、FEUA以及CUA呈明显下降趋势;FEUA、CUA、UUA/Ucr与SUA水平呈负相关 (P<0.05);多元回归分析示年龄和餐后胰岛素均与24hUUA呈负相关,空腹胰岛素与FEUA呈负相关,餐后胰岛素与CUA呈负相关。 2. 不同浓度胰岛素培养HK-2细胞URAT1的mRNA和蛋白表达较空白对照组明显升高,且随时间延长及胰岛素浓度增加而呈递增趋势(均P<0.05),URAT1 在胰岛素100 nM干预48小时表达量达到高峰;与对照组比较,高浓度胰岛素(100 nM)可以增加p-Akt1蛋白的表达(P<0.05);3.随氯沙坦浓度的增高,URAT1表达逐渐下降,与高胰岛素组存在明显差异(P<0.01);与高胰岛素组比较,氯沙坦100 μM干预后p-Akt1及URAT1的表达下降(P<0.05),应用LY294002干预后p-Akt1及URAT1的表达显著下降(P<0.01),且其效应较而氯沙坦干预组更强(P<0.05)。 结论:1. 血胰岛素水平升高是抑制肾小管尿酸排泄的主要影响因素。2. 胰岛素可通过时间与浓度依赖性的方式诱导人肾小管上皮细胞URAT1的表达。3.氯沙坦可经部分抑制肾小管上皮细胞PI3K/Akt1信号通路的活性而抑制高胰岛素诱导的HK-2细胞URAT1上调表达,从而在伴高胰岛素血症状态的MetS所致血尿酸升高或高尿酸血症中起到抑制肾小管对尿酸的重吸收而降低血尿酸的作用。
Other AbstractObjectives: To provide basis for both the precise mechanisms and prevention of hyperuricemia related to metabolic syndrome in the state of insulin resistance or hyperinsulinaemia. Results: 1. FEUA showed a distinct decreasing trend along with elevating of the FIns level. 24hUUA、FEUA and CUA showed a distinct decreasing trend along with elevating of the 2h PIns level. FEUA, CUA and UUA/Ucr were negatively correlated with SUA levels (P<0.05). Multivariate regression analysis of the influence factors about renal uric acid excretion. Age and 2hPIns was negatively correlated with 24hUUA. PBG was positively correlated with FEUA but FIns was the opposite. eGFR and PBG were positively correlated with CUA but 2hPIns was the opposite. 2. RT-PCR and Western Blot results revealed that URAT1 mRNA and protein expression in different concentrations of insulin groups were higher than that in control group. Insulin induced URAT1 mRNA and protein up-expression in a time- and dose-dependent manner (P<0.05). The levels of phosphorylated Akt1 increased in HK-2 cells when exposured to insulin (100 nM) for 48 hrs (P<0.05, compared with control). 3. Losartan down-regulated the insulin-induced expression of URAT1 protein in a dose-dependent manner (P<0.01). Compared with control group, the expression of URAT1 and p-Akt1 but not Akt1 protein induced by high insulin increased significantly in HK-2 cells (P<0.05). The effect of Losartan was weaker than that of LY294002 between two groups. Conclusions: 1. Elevated serum insulin levels was a primary influence factor for renal underexcretion of uric acid. 2. Insulin could induce URAT1 expression in a time- and dose-dependent manner in cultured HK-2 cells. This indicated that high insulin may increase SUA levels by up-regulating URAT1 expression and then increasing reabsorption of UA at renal tubular epithelial cells. 3. Losartan might down-regulate the high insulin-induced URAT1 expression by partly inhibiting the active of PI3K/Akt1 pathway in HK-2 cells. Losartan play its uricosuric action by reducing proximal tubular reabsorption of uric acid which leading to decreased serum uric acid concentrations in patients with the MetS related hyperuricemia.
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Language中文
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/223440
Collection学院待认领
Affiliation临床医学院
Recommended Citation
GB/T 7714
黄文辉. 高胰岛素抑制肾脏尿酸排泄的基础与临床研究以及氯沙坦的干预机制[D]. 兰州. 兰州大学,2015.
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